A personal history of non-melanoma skin cancer (NMSC) is associated with an increased subsequent risk of both non-cutaneous malignancies and cutaneous and mucosal cancers. The basis for this observation remains unclear, but the risk of subsequent non-skin cancers suggests a high cancer-risk phenotype. A likely candidate underlying this susceptibility to both cutaneous and non-cutaneous malignancies is inter-individual differences in DNA repair. Because of the strong link between Nucleotide Excision Repair (NER) and NMSC, and because of the importance of bulky DNA adducts to all cancers, the NER pathway is the most relevant DNA repair pathway. We hypothesize that polymorphisms in genes in the NER pathway may be the underlying susceptibility factor. We will test this hypothesis in a prospective cohort study (CLUE II) of 28,594 persons who will have been followed-up for 19 years (through 2009) for the occurrence of cancer. The cohort will be genotyped (using blood collected at baseline in 1989) for 75 polymorphisms in 26 NER genes. The specific aim addresses the joint role of genetic alterations in the NER pathway and history of NMSC on subsequent non-NMSC cancer. Using time-to-event analyses, the influence of NER genotypes on cancer risk will be assessed in those with and without a personal history of NMSC. In addition to haplotype analysis, a novel statistical approach, logic regression, will be used to comprehensively assess the potential interactions within the NER pathway. The proposed study builds on pilot data from a subset of individuals in the cohort indicating an increased risk of subsequent cancer in persons with a history of NMSC who had ERCC2./XPD Lys751GIn Lys/GIn or Gin/Gin genotypes. Based on a strong scientific rationale, the hypothesis links an epidemiologic observation of a high cancer-risk NMSC phenotype with genetic variation in the NER pathway. The approach of using a prospective cohort study holds distinct advantages over case-control studies. Translation of the expected results will lead to better identification of at risk populations who should be considered for prevention interventions.